RESUMO
The benefit of azacitidine treatment in survival of high-risk myelodysplastic syndromes (MDS) patients compared with conventional care treatment (CCT) has not been established outside clinical trials. To assess its effectiveness, we compared overall survival (OS) between azacitidine and conventional treatment (CCT) in high-risk MDS patients, excluding those undergoing stem cell transplantation, submitted to the Spanish MDS registry from 2000 to 2013. Several Cox regression and competing risk models, considering azacitidine as a time-dependent covariate, were used to assess survival and acute myeloblastic leukemia (AML) progression. Among 821 patients included, 251 received azacitidine. Median survival was 13.4 (11.8-16) months for azacitidine-treated patients and 12.2 (11-14.1) for patients under CCT (P=0.41). In a multivariate model, age, International prognostic scoring system and lactate dehydrogenase were predictors of OS whereas azacitidine was not (adjusted odds ratio 1.08, 95% confidence interval 0.86-1.35, P=0.49). However, in patients with chromosome 7 abnormalities, a trend toward a better survival was observed in azacitidine-treated patients (median survival 13.3 (11-18) months) compared with CCT (median survival 8.6 (5-10.4) months, P=0.08). In conclusion, our data show that, in spite of a widespread use of azacitidine, there is a lack of improvement in survival over the years. Identification of predicting factors of response and survival is mandatory.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/etiologia , Masculino , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Prognóstico , Sistema de Registros , Espanha/epidemiologia , Resultado do TratamentoAssuntos
Neoplasias do Sistema Nervoso Central , Infiltração Leucêmica , Sarcoma Mieloide , Neoplasias da Medula Espinal , Medula Espinal/patologia , Feminino , Humanos , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/terapia , Infiltração Leucêmica/patologia , Infiltração Leucêmica/terapia , Pessoa de Meia-Idade , Indução de Remissão , Sarcoma Mieloide/patologia , Sarcoma Mieloide/terapia , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/terapiaRESUMO
Patients with isolated del(5q) and MDS are considered to have good prognosis as compared to other MDS subtypes. Most patients suffered of anemia and 50% of them required transfusions at diagnosis. It is known that for patients with MDS and del(5q) in transfusion dependence(TD), Lenalidomide is the first choice treatment. However, there are no data regarding natural evolution of anemia in patients diagnosed in MDS and del(5q) without TD, factors that may impact on the development of TD or disease outcome. In the present study we have performed a retrospective multicenter analysis on 83 patients with low-int 1 MDS and del(5q) without TD. During the study 61 patients became TD at a median of 1.7 years and only the Hb level 9 g/dL was associated with poorer TFS (p = 0.007) in the multivariate analysis. Among these 61 TD patients, 49 received treatment (19 Lenalidomide). Median follow up was 48 months, estimated OS at 2 and 5 year was 92% and 50% respectively. In the multivariate analysis for OS, platelets <100,000 mm(-3) and Lenalidomide treatment retained the statistical significant impact. LFS at 2 and 5 years was 86% and 73% respectively, and median time to sAML was 8.16 years (CI 95%: 6.05-10.27). In the multivariate analysis only thrombocytopenia retained statistical significance. In summary, this retrospective study show that level of Hb is an important parameter in order to determine the time until TD, it should be also stressed the importance of an early treatment in order to prevent TD development and shorter survival.
Assuntos
Anemia/diagnóstico , Transfusão de Sangue/estatística & dados numéricos , Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Anemia/mortalidade , Anemia/terapia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Progressão da Doença , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Fatores de TempoRESUMO
The severity of neutropenia in myelodysplastic syndrome (MDS) has not been completely studied. We analyzed the prognostic significance of severe neutropenia (neutrophils count <0.5×10(9)/L) at diagnosis in 1109 patients with de novo MDS and low/intermediate-1 IPSS included in the Spanish MDS Registry. Severe neutropenia was present at diagnosis in 48 of 1109 (4%). Patients with severe neutropenia were most strongly represented within the groups of refractory cytopenia with multilineage dysplasia (40%) and refractory anemia with excess of blast type 1 (29%). Severe neutropenia had negative effects on the low/intermediate-1 risk group. A significant difference in overall survival was observed between patients with severe neutropenia (28 months) and patients with a neutrophil count higher than 0.5×10(9)/L (66 months) (p<0.0001). Also, severe neutropenia predicted a significantly reduced on leukemia-free survival (p<0.0001). In the multivariate analysis, severe neutropenia retained its independent prognostic influence on overall survival [HR: 2.19, 95% CI (1.41-3.10), p<0.0001] and leukemia free survival [HR: 3.51, 95% CI (1.97-6.26), p<0.0001]. The degree of neutropenia should be considered as additional prognostic factor in low/intermediate-1 IPSS MDS.
Assuntos
Anemia Refratária/complicações , Síndromes Mielodisplásicas/complicações , Neutropenia/diagnóstico , Neutropenia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Estadiamento de Neoplasias , Neutropenia/mortalidade , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
La trombocitopenia fetal/neonatal aloinmune (TFNA) es la causa más frecuente de trombocitopenia grave en el recién nacido. Es un proceso agudo donde las plaquetas fetales son destruidas durante la gestación por un anticuerpo de tipo IgG presente en la madre aloinmunizada. En la raza caucásica, tiene especificidad frente al antígeno específico plaquetar HPA-1a en más del 80% de los casos. La hemorragia intracraneal, que ocurre hasta en un 30%, es la complicación más grave, con un 10% de mortalidad y un 20% de secuelas neurológicas irreversibles. El alto riesgo de repetición de hemorragia grave en futuras gestaciones obliga a plantearse profilaxis o tratamiento antenatal. El diagnóstico precoz puede permitir administrar un tratamiento eficaz basado en la transfusión de plaquetas de fenotipo HPA compatible o de inmunoglobulinas endovenosas. Presentamos el caso de una gestante de 27 años, que en la semana 35 de su segunda gestación fue diagnosticada por ecografía de hidrocefalia fetal bilateral. En la cesárea realizada en la semana 36, el neonato presentó hematomas en hombro y glúteo izquierdos, macrocefalia con fontanelas a tensión y salida de líquido cefalorraquídeo hemorrágico tras la colocación de un catéter de derivación externo. El hemograma reveló trombocitopenia grave (9 x 109/L). Ante sospecha clínica de TFNA, se transfundieron plaquetas de donante no fenotipado para el HPA-1a y se inició tratamiento con inmunoglobulinas endovenosas, con recuperación de la trombocitopenia, pero con secuelas neurológicas probablemente irreversibles. El estudio inmunohematológico confirmó el fenotipo materno HPA-1a negativo, el fenotipo neonatal HPA-1a positivo y la presencia de aloanticuerpos anti-HPA-1a en el suero materno. La profilaxis y el tratamiento continúan siendo, en la actualidad, motivo de discusión y controversia, así como la posibilidad de realizar un cribado antenatal (AU)
Foetal/neonatal alloimmune thrombocytopenia is the most common cause of severe thrombocytopenia in the newborn. It is an acute disorder which implies that foetal platelets are destroyed during the pregnancy due to a maternal alloimmune IgG antibody. More than 80% of Caucasians are HPA-1a specific. Intracranial haemorrhage, which occurs in 30% of cases, is the most serious complication, with a 10% mortality rate or a 20% rate of irreversible neurological sequels. The high risk of a recurrence of serious bleeding in future pregnances led us to consider prophylaxis or prenatal treatment. An early diagnosis of this process allows an effective therapy to be carried out based on the infusion of compatible phenotype HPA platelets or endovenous immunoglobulins. We present the case of a 27 year old pregnant woman, who in the 35th week of a second pregnancy was diagnosed using echography with a bilateral foetal hydrocephaly. After caesarean delivery in the 36th week, the newborn presented haematomas in the left shoulder and gluteus, macrocephalia with tension of the fontanellas and hemorrhagic cerebrospinal fluid after insertion of an external ventricular derivation catheter. The haemogram revealed a severe trombocytopenia (9 x 109/L). In the light of clinical suspicion of foetal/neonatal alloimmune thrombocytopenia, infusion was made of platelets from a non-phenotyped donor for the HPA-1a system, and an endovenous immunoglobulin treatment was followed, with a recovery of platelet counts, but with neurological sequels that are probably irreversible. The immunohaematologal study confirmed the negative HPA-1a maternal phenotype, the neonatal HPA-1a positive phenotype and the presence of anti-HPA-1a alloantibodies in the maternal serum. Nowadays, the prophylaxis and treatment continue to be a controversial issue that is open to discussion, as is the possibility of implementing antenatal screening (AU)
Assuntos
Humanos , Gravidez , Adulto , Feminino , Trombocitopenia/complicações , Trombocitopenia/epidemiologia , Imunoglobulinas/uso terapêutico , Programas de Rastreamento , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico , Autoimunidade/fisiologia , Hemorragias Intracranianas/epidemiologia , Trombocitopenia/etiologia , Autoimunidade , Autoimunidade/imunologia , Técnica Direta de Fluorescência para Anticorpo/métodosRESUMO
The World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues (2001) defined a provisional entity named refractory anemia with ringed sideroblasts associated to marked thrombocytosis (RARS-MT). Diagnosis of RARS-MT requires more than 15% of ringed sideroblasts in bone marrow aspirate and the existence of a thrombocytosis in blood, with a platelet count above 600 x 10(9)/L. Nevertheless, controversy exists regarding this platelet count "cut-off" value and, when RARS-MT was defined, the JAK2 mutation and its importance in the study of myeloproliferative disorders was unknown. We present the results of a Spanish retrospective multicentric study, which includes 76 cases of RARS with associated thrombocytosis (platelet count above 400 x 10(9)/L) at diagnosis (RARS-T), 36 of them with a platelet count above 600 x 10(9)/L. Our aim was to analyze their clinical, analytical and morphological characteristics, and to establish correlations with the JAK2 mutational status.
Assuntos
Anemia Refratária/genética , Anemia Refratária/patologia , Janus Quinase 2/genética , Mutação de Sentido Incorreto , Trombocitose/genética , Trombocitose/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Anemia Refratária/sangue , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Trombocitose/sangueRESUMO
Foetal/neonatal alloimmune thrombocytopenia is the most common cause of severe thrombocytopenia in the newborn. It is an acute disorder which implies that foetal platelets are destroyed during the pregnancy due to a maternal alloimmune IgG antibody. More than 80% of Caucasians are HPA-1a specific. Intracranial haemorrhage, which occurs in 30% of cases, is the most serious complication, with a 10% mortality rate or a 20% rate of irreversible neurological sequels. The high risk of a recurrence of serious bleeding in future pregnancies led us to consider prophylaxis or prenatal treatment. An early diagnosis of this process allows an effective therapy to be carried out based on the infusion of compatible phenotype HPA platelets or endovenous immunoglobulins. We present the case of a 27 year old pregnant woman, who in the 35th week of a second pregnancy was diagnosed using echography with a bilateral foetal hydrocephaly. After caesarean delivery in the 36th week, the newborn presented haematomas in the left shoulder and gluteus, macrocephalia with tension of the fontanellas and hemorrhagic cerebrospinal fluid after insertion of an external ventricular derivation catheter. The haemogram revealed a severe trombocytopenia (9 x 109/L). In the light of clinical suspicion of foetal/neonatal alloimmune thrombocytopenia, infusion was made of platelets from a non-phenotyped donor for the HPA-1a system, and an endovenous immunoglobulin treatment was followed, with a recovery of platelet counts, but with neurological sequels that are probably irreversible. The immunohaematologal study confirmed the negative HPA-1a maternal phenotype, the neonatal HPA-1a positive phenotype and the presence of anti-HPA-1a alloantibodies in the maternal serum. Nowadays, the prophylaxis and treatment continue to be a controversial issue that is open to discussion, as is the possibility of implementing antenatal screening.
Assuntos
Hemorragias Intracranianas/etiologia , Trombocitopenia Neonatal Aloimune , Adulto , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Recém-Nascido , Hemorragias Intracranianas/mortalidade , Hemorragias Intracranianas/terapia , Contagem de Plaquetas , Transfusão de Plaquetas , Gravidez , Trombocitopenia Neonatal Aloimune/diagnóstico , Trombocitopenia Neonatal Aloimune/terapiaRESUMO
We have carried out a high-resolution whole genome DNA profiling analysis on 100 bone marrow samples from a consecutive series of de novo acute myeloid leukemia (AML) cases. After discarding copy number changes that are known to be genetic polymorphisms, we found that genomic aberrations (GA) in the form of gains or losses of genetic material were present in 74% of the samples, with a median of 2 GA per case (range 0-35). In addition to the cytogenetically detected aberration, GA were present in cases from all cytogenetic prognostic groups: 79% in the favorable group, 60% in the intermediate group (including 59% of cases with normal karyotype) and 83% in the adverse group. Five aberrant deleted regions were recurrently associated with cases with a highly aberrant genome (e.g., a 1.5 Mb deletion at 17q11.2 and a 750 kb deletion at 5q31.1). Different degrees of genomic instability showed a statistically significant impact on survival curves, even within the normal karyotype cases. This association was independent of other clinical and genetic parameters. Our study provides, for the first time, a detailed picture of the nature and frequency of DNA copy number aberrations in de novo AML.
Assuntos
Instabilidade Genômica , Leucemia Mieloide/genética , Análise de Sequência com Séries de Oligonucleotídeos , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea , Análise Citogenética , Dosagem de Genes , Humanos , Leucemia Mieloide/diagnóstico , Pessoa de Meia-Idade , Mutação , Prognóstico , RiscoAssuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 2/genética , Amplificação de Genes , Leucemia Mieloide Aguda/genética , Idoso , Idoso de 80 Anos ou mais , Evolução Biológica , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteína de Leucina Linfoide-Mieloide , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcr , Proto-Oncogenes/genética , Receptores de Glutamato/genética , Fatores de Transcrição/genéticaRESUMO
Midges of the genus Culicoides (Diptera: Ceratopogonidae) were trapped weekly from May 2001 through December 2002 on two farms in the province of Barcelona (Spain). Dosrius farm was stocked with sheep and goats whereas Bellaterra farm had only sheep. This trapping programme was carried out within the framework of an investigation into the occurrence/absence of possible vectors of bluetongue virus (BTV) in mainland Spain. A total of 30,079 Culicoides specimens were collected from 165 light trap collections, comprising nine species: C. obsoletus (Meigen), C. pulicaris (Linnaeus), C. circumscriptus Kieffer, C. newsteadi Austen, C. imicola Kieffer, C. scoticus Downes & Kettle, C. punctatus (Meigen), C. pallidicornis Kieffer and C. flavipulicaris Dzhafarov. The last five are new to Catalonia, C. pallidicornis is also new to Spain and C. flavipulicaris is new to Iberia. The seasonal occurrence of these species is described here. Of those species, C. imicola is the main BTV and African horse sickness virus (AHSV) vector in Europe, whereas species belonging to the so-called Obsoletus group (C. obsoletus and C. scoticus in our study) are considered to be potential vectors for BTV.
Assuntos
Vírus Bluetongue/isolamento & purificação , Ceratopogonidae/classificação , Ceratopogonidae/virologia , Insetos Vetores , Animais , Feminino , Masculino , Estações do Ano , EspanhaRESUMO
Cytogenetic analysis is useful in the diagnosis and to assess prognosis of B-cell chronic lymphocytic leukemia (B-CLL). However, successful cytogenetics by standard techniques has been hindered by the low in vitro mitotic activity of the malignant B-cell population. Fluorescence in situ hybridization (FISH) has become a useful tool, but it does not provide an overall view of the aberrations. To overcome this hurdle, two DNA-based techniques have been tested in the present study: comparative genomic hybridization (CGH) and amplotyping by arbitrarily primed PCR (AP-PCR). Comparative genomic hybridization resolution depends upon the 400-bands of the human standard karyotype. AP-PCR allows detection of allelic losses and gains in tumor cells by PCR fingerprinting, thus its resolution is at the molecular level. Both techniques were performed in 23 patients with stage A B-CLL at diagnosis. The results were compared with FISH. The sensitivity of AP-PCR was greater than CGH (62% vs. 43%). The use of CGH combined with AP-PCR allowed to detect genetic abnormalities in 79% (15/19) of patients in whom G-banding was not informative, providing a global view of the aberrations in a sole experiment. This study shows that combining these two methods with FISH, makes possible a more precise genetic characterization of patients with B-CLL.
Assuntos
Amplificação de Genes , Leucemia Linfocítica Crônica de Células B/genética , Reação em Cadeia da Polimerase/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Impressões Digitais de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Sensibilidade e EspecificidadeAssuntos
Artrite Juvenil/complicações , Doenças do Sistema Imunitário/etiologia , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/patologia , Pré-Escolar , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/patologia , Ativação de Macrófagos/imunologia , Masculino , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Síndrome , Resultado do TratamentoRESUMO
Our aim was to evaluate the clinical use of cytogenetic analysis as a prognostic factor in the outcome of newly diagnosed multiple myeloma (MM) patients. The present series includes 111 newly diagnosed MM patients treated with one of three standard-dose regimens or autologous transplantation over an 8-year time interval. As expected, the presence of an abnormal karyotype (39% of patients) correlated with poor prognosis (progression rate 63% v 47%, P = 0.042), shorter event-free (EFS, P = 0.014) and overall (OS, P = 0.005) survival. Two distinct cytogenetic abnormalities were the most significant variables that influenced EFS and OS in the univariate analysis. The presence of hypodiploid karyotypes or rearrangements of band 22q11 were associated with higher progression rate (P = 0.001) and shorter EFS (P < 0.024) and OS (P < 0.004). The median EFS and OS for patients with hypodiploidy was 4 and 7 months respectively. Multivariate analysis showed that absence of hypodiploidy was the most favourable prognostic variable for OS (P = 0.022) followed by stage < or = IIA, serum calcium < or = 2875 micromol/l, and absence of abnormalities 22q. The data suggest that the presence of hypodiploid karyotypes and rearrangements on 22q11 band show a higher progression rate and shorter survival in MM patients.
Assuntos
Aberrações Cromossômicas , Diploide , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Rearranjo Gênico , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , PrognósticoAssuntos
Bancos de Sangue/organização & administração , Antígenos de Grupos Sanguíneos/imunologia , Eritrócitos/imunologia , Transfusão de Sangue/estatística & dados numéricos , Controle de Formulários e Registros , Necessidades e Demandas de Serviços de Saúde , Humanos , Imunofenotipagem , Relações Interinstitucionais , EspanhaRESUMO
Cytogenetic analysis of unstimulated short-term bone marrow cell cultures was performed on 280 patients with multiple myeloma and related disorders. In 65% of the cases, an additional short term B-cell stimulated culture was also examined. Chromosomally abnormal clones were found in 31% of the patients, 15% in Waldenström macroglobulinemia. 25% in monoclonal gammopathies, 33% in multiple myeloma, and 50% in plasma cell leukemia. Three primary chromosomal breakpoints were recurrently involved: 14q32, 16q22, and 22q11. Structural rearrangements of chromosome 1 were the most frequent (26% of the abnormal cases), but always as a secondary change. Rearrangements of band 14q32 were found in 22% of the abnormal cases. Among the multiple myeloma patients who showed an abnormal karyotype, 33 (46%) were hyperdiploid, most frequently, with 52-56 chromosomes, 29 patients (40%) were pseudodiploid, and the remaining 12 cases (14%) were hypodiploid. A highly significant relation was observed between the presence of an abnormal karyotype and the following clinical parameters: stage III (P = 0.0001), bone marrow plasma cell infiltration greater than 30% (P = 0.0001), presence of bone lesions (P = 0.0009), and beta 2-microglobulin levels greater than 4 mg/L (P = 0.0001).
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos , Mieloma Múltiplo/genética , Fragilidade Cromossômica , Humanos , Cariotipagem , Leucemia Plasmocitária/genética , Células Tumorais Cultivadas , Macroglobulinemia de Waldenstrom/genéticaRESUMO
PURPOSE: To evaluate and establish a relationship between serum ferritin value and haemoglobin level, serum iron or transferrin in volunteer blood donors. MATERIAL AND METHODS: We have studied a group of 479 blood donors from Navarra's Health Area V, whose blood cell examination, iron, ferritin and transferrin values were determined. We classified these donors in 4 groups according to their ferritin concentration (ng/mL): f1 (0-12), f2 (13-20), f3 (21-400) and f4 (more than 400). The results were analyzed by the statistical program SPSS/PC+. The sensitivity, specificity, accuracy and predictive value of the positive test, for the determination of haemoglobin level as an indicator of iron deposits were calculated. RESULTS: The comparative statistical study of all these groups indicated that there were significant differences in the ferritin and the haemoglobin values (p < 0.001 and p < 0.05, respectively), except between f1 and f2, which only presented and intergroup difference in the ferritin values. In blood donors, the estimation of iron deposits from the hemoglobin level showed a diagnostic sensitivity greater than 90%. CONCLUSIONS: Haemoglobin values would allow the selection of those donors that could have an iron deficiency, or a borderline concentration; nevertheless, it would not allow the distinction between these two groups. This last observation is not important because donors that show a ferritin value lower than 20 ng/mL should not give blood. When the ferritin is greater than 20 ng/mL in men, the iron deposits will be adequate in 97% of them. This percentage is about 90 in women whose haemoglobin level is greater than 12.5 g/dL. Therefore, we consider that haemoglobin values present a good cost/benefit ratio for donor selection.